Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

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Progress in Neuro-Psychopharmacology & BiologicalPsychiatry

Involvement of the dorsolateral prefrontal cortex and superior temporalsulcus in impaired social perception in schizophrenia

Jung Eun Shin a,b, Soo-Hee Choi c, Hyeongrae Lee d, Young Seok Shin e, Dong-Pyo Jang e, Jae-Jin Kim a,b,f,⁎a Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Koreab Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Koreac Department of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Koread Magnetoencephalography center, Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Koreae Department of Biomedical Engineering, Hanyang University, Seoul, Republic of Koreaf Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea

Abbreviations: fMRI, functionalmagnetic resonance imfrontal cortex; STS, superior temporal sulcus; DMPFC, dortemporo-parietal junction; DSM-IV-TR, Diagnostic andTest-Revised; RPM, Raven's progressive matrices; SAS, SPositive and Negative Syndrome Scale; SC-LFS, Strauss–Scale; TE, echo time; TR, repetition time; BOLD, blood oxyg⁎ Corresponding author at: Department of Psychiatry

211 Eonju-ro, Gangnam-gu, Seoul, 135–720, Republic offax: +82 2 3462 4304.

E-mail address: jaejkim@yonsei.ac.kr (J.-J. Kim).

http://dx.doi.org/10.1016/j.pnpbp.2014.12.0060278-5846/© 2014 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 12 September 2014Received in revised form 5 December 2014Accepted 19 December 2014Available online 27 December 2014

Keywords:Daily lifeDorsolateral prefrontal cortexSchizophreniaSocial perceptionSuperior temporal sulcus

Background: Schizophrenia is a mental disorder characterized by impairments in diverse thinking and emotionalresponses, which are related to social perception dysfunction. This fMRI study was designed to investigate aneurobiological basis of social perception deficits of patients with schizophrenia in various social situations ofdaily life and their relationship with clinical symptoms and social dysfunction.Methods: Seventeen patients and 19 controls underwent functional magnetic resonance imaging, during whichparticipants performed a virtual social perception task, containing an avatar's speech with positive, negative orneutral emotion in a virtual reality space. Participants were asked to determine whether or not the avatar'sspeech was appropriate to each situation.Results: The significant group × appropriateness interaction was seen in the left dorsolateral prefrontal cortex(DLPFC), resulting from lower activity in patients in the inappropriate condition, and left DLPFC activity wasnegatively correlated with the severity of negative symptoms and positively correlated with the level of social

functioning. The significant appropriateness × emotion interaction observed in the left superior temporal sulcus(STS) was present in controls, but absent in patients, resulting from the existence and absence of a differencebetween the inappropriate positive and negative conditions, respectively.Conclusions: These findings indicate that dysfunction of the DLPFC-STS networkmay underlie patients' abnormalsocial perception in various social situations of daily life. Abnormal functioning of this networkmay contribute toincreases of negative symptoms and decreases of social functioning.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Schizophrenia is a mental disorder characterized by impairment inthinking and emotional responses. Clinical symptoms including posi-tive, negative and disorganized symptoms as well as various cognitivedeficits lead to social dysfunction, such as ineffective social interaction,poor social skills and the inability to remain employed (Boden et al.,

aging; DLPFC, dorsolateral pre-somedial prefrontal cortex; TPJ,Statistical Manual, 4th Edition,ocial Anhedonia Scale; PANSS,Carpenter Level of Functioningen level dependent., Gangnam Severance Hospital,Korea. Tel.: +82 2 2019 3341;

2009; Weinberg et al., 2009). Social dysfunction in schizophrenia maybe lifelong and predictive of longer hospitalization (Olfson et al., 2011).In particular, deficits in social cognition including social perception havebeen linked to poor functional outcome in schizophrenia (Mancusoet al., 2011). Social perception involves the ability to identify socialroles, rules and context and to make inferences about complex or am-biguous social situations (Green et al., 2008; Penn et al., 2002). Socialperception is the first step in social cognition, and it is further involvedin processes of organizing behavioral responses directly or indirectly(Norman, 2002), suggesting that abnormal behaviors observed inschizophrenia may be initiated by impaired social perception.

To understand social perception, previous researchers have usedvarious stimuli. Human faces are frequently used stimuli because theyare the basic component of social perception and provide diverse infor-mation for social communication (Kanwisher et al., 1997; Marwick andHall, 2008). Patients with schizophrenia have deficits in both face andfacial affect recognition with less accurate and slower responses thancontrol participants (Green and Phillips, 2004; Hooker and Park, 2002),

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82 J.E. Shin et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

and they have functional abnormalities in the fusiform gyrus during thefacial information processing (Quintana et al., 2003). Another usefulmethod is biological motion. Patients with schizophrenia have impairedgaze discrimination with longer reaction time and hyper-perception(Franck et al., 2002; Tso et al., 2012) and often show difficulties in dis-criminating biological motion due to abnormalities in the superior tem-poral sulcus (STS) and inferior parietal lobe (Kim et al., 2011b; Spenceret al., 2013; Thakkar et al., 2014). In particular, the STS is involved in un-derstanding other people's actions and intentions (Pelphrey et al., 2004)and has been considered to be one of the core regions for the interactionof social perception and emotional processing (Kramer et al., 2010;Norris et al., 2004).

While perceiving others' behaviors in social situations, patients withschizophrenia showdysfunction in the intention network, including thedorsomedial prefrontal cortex (DMPFC) and temporo-parietal junction(TPJ) (Bara et al., 2011; Walter et al., 2009). In addition, patients withschizophrenia have shown aberrant responses in the occipital andtemporal regions while processing situational pictures as social cues(Bjorkquist and Herbener, 2013), marked decreases in dorsolateralprefrontal cortex (DLPFC) activation during audiovisual integration(Szycik et al., 2009), and ventral premotor dysfunction during video-watching (Ebisch et al., 2013; Park et al., 2009). Particularly, giventhat the DLPFC plays an important role in cognitive control in socialsituations (Weissman et al., 2008), DLPFC hypofunction may be a lead-ing factor regarding dysfunctional social perception in patients withschizophrenia.

Despite the accumulation of vast amount of knowledge, social per-ception remains an actively studied area because of its complexity anddiversity.More complex social situations have been increasingly neededto discover how the brain works with a plethora of stimuli. Since the1990s, several behavioral studies have used social situations as a stimu-lus. The examples are the social feature recognition test (Corrigan et al.,1996) and the social cue recognition videotaped test (Corrigan andNelson, 1998), demonstrating that patients with schizophrenia areless accurate in situational feature recognition or social cue recognitionthan controls. Recently, it has been reported that these deficits in socialperceptionmay be related to abnormal eye gaze in interactive social sit-uations (Choi et al., 2010). However, complex social situations havenever been used in a functional magnetic resonance imaging (fMRI)study. It therefore remains unclear how the brain mechanism of deficitsin social perception underlies the experiences of patients with schizo-phrenia in their daily lives. This unclear mechanism can be addressedby an fMRI study using a virtual reality task reflecting social perceptionin daily lives, as virtual reality provides an immersive environment sim-ulating complex social situations (Choi et al., 2010; Han et al., 2009). Infact, virtual reality tasks using avatars have been used to assess patients'behavioral and emotional characteristics objectively and to train pa-tients to cope effectivelywith various social situations (Kim et al., 2008).

This fMRI study was designed to investigate a neurobiological basisof social perception deficits in schizophrenia using social situationsthat patients would face in their daily lives. For these purposes, wedeveloped a virtual social perception task in which participants wereasked to determine the appropriateness of various ways of speech indifferent social situations. In this study using dynamic stimuli and func-tional outcome measures, we hypothesized that patients with schizo-phrenia would show altered activation in various social perception-related regions including the prefrontal cortex and STS, and that thedegree of altered activation would be correlated with the clinical andsocial functioning scale scores.

2. Methods

2.1. Participants and clinical measurements

Seventeen patients with schizophrenia and 19 healthy control sub-jects participated in this study. All patients met the DSM-IV-TR criteria

for schizophrenia without other comorbid psychiatric disorders andwere taking antipsychotics with a mean chlorpromazine-equivalentdosage of 503.3 ± 226.4 mg. The Structural Clinical Interview forDSM-IV (First et al., 1996) was used for the diagnosis of schizophreniain patients, who were recruited in the psychiatric outpatient clinic,and the exclusion of any psychiatric disorders in controls, whowere re-cruited by poster advertisements. Any subjects with a past or presenthistory of medical or neurological illness or with left-handedness wereexcluded. After a complete description of this study was presented, allsubjects gave written informed consent to the protocols, which wereapproved by the local institutional review board.

Participants' general intellectual ability was measured by theRaven's progressive matrices (RPM) (Raven, 1990), and the ability toexperience pleasure from social stimuli was measured by the SocialAnhedonia Scale (SAS) (Chapman et al., 1976). In addition, the clinicalstatus of each patient was measured using the Positive and NegativeSyndrome Scale (PANSS) (Kay et al., 1987) for the severity of schizo-phrenic symptoms and the Strauss–Carpenter Level of FunctioningScale (SC-LFS) (Strauss and Carpenter, 1972) for various domains ofsocial functioning such as social contacts, useful work and fullness oflife.

2.2. Experimental design

Participants performed the virtual social perception task during fMRIscanning. As shown in Fig. 1, social situations were created in a virtualreality space in which an avatar made conversation with someone. Par-ticipants were asked to determine whether or not the avatar's speechwas appropriate to the situation by pressing a corresponding button.The task consisted of 126 experimental trials; therewere 21 real-life sit-uations that each included six different conditions. The avatar's speechwas either well or poorly matched to the situation, in 63 appropriateand 63 inappropriate conditions, respectively, and was emotionallypositive, negative or neutral, in 42 positive, 42 negative, and 42 neutralconditions, respectively. The trials were presented randomly in anevent-related design. Each trial consisted of listening to the avatar'sspeech for 3 s, followed by 1 s of silence during which participantswere expected to respond, and seeing a screen with a cross on a blackbackground for 1 s. Null events were added in varying durations of0.625 to 7.5 s, and the total session time was approximately 14 min.

2.3. MRI acquisition and analysis

The fMRI experiment was conducted on a research-dedicated,whole-body, 1.5 T MRI system (Sigma Eclipse; GE Medical Systems,Milwaukee, WI, USA) using a standard quadrature, bird-cage headcoil. Functional images were obtained using an echo planar imaging se-quence (matrix size=64× 64, number of slices= 30, slice thickness=5mm, spatial resolution=3.75 × 3.75 × 5mm3, TE=22ms, TR=2.5 s,field of view = 240 mm, flip angle = 90°). High-resolution anatomicalimages were obtained using a gradient echo sequence (matrix size =256 × 256, number of slices = 115, slice thickness = 1.5 mm, spatialresolution = 0.94 × 0.94 × 1.5 mm3, TE = 1.8 ms, TR = 8.5 ms, fieldof view = 240 mm, flip angle = 12°) after the functional scans.

Imageswere preprocessed using SPM8 (Welcome Institute of Cogni-tive Neurology, London, UK; www.fil.ion.ucl.ac.uk/spm), and bad sliceswere detected and discarded using ArtRepair software (Mazaika et al.,2005). After correcting for differences in slice acquisition time andhead motion, the functional images were co-registered to the T1-weighted image. The co-registered images were spatially normalizedusing the transformation functions, which were obtained by normaliz-ing the T1-weighted image to the standard T1 template using nonlineartransformation. These normalized imageswere smoothed by a Gaussiankernel of 8mmfull-width-half-maximum.Ahigh-passfilter (128 s)wasapplied on the image time series to eliminate low frequency signals.

http://www.fil.ion.ucl.ac.uk/spm

Fig. 1. An example of the experimental stimuli. In a scene of “at the kiosk,” a woman says something to a storekeeper for 3 s. As shown on the right side, there are six different trials perscene. In the appropriate positive condition (APP-POS), her statement (“Thanks. I hope you to sell a lot!”) is positive and well matched with the situation. On the other hand, in theinappropriate positive condition (INA-POS), she says “Help yourself to as much as you want,” and this statement is positive, but unmatched with the situation. Four other trials includedthe appropriate negative (APP-NEG), inappropriate negative (INA-NEG), appropriate neutral (APP-NEU), and inappropriate neutral (INA-NEU) conditions. Twenty other scenes with sixconditions were used to express diverse social situations.

83J.E. Shin et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

Functional data were analyzed using a general linear model. To ex-clude activities related to the processing of neutral emotion, individualcontrast maps were generated by contrasting positive or negative emo-tional events with neutral ones at the first-level analysis. The resultingset of contrast images were then entered into a second-level analysisusing a flexible factorial model. The activationmaps for themain effectsand interactionswere analyzed by a 2 (group: patients and controls) × 2(appropriateness: appropriate and inappropriate) × 2 (emotion; posi-tive and negative) flexible factorial model. In addition, the appropriate-ness × emotion interaction was analyzed in each group. For thecomparison between trial types, activation was determined by uncor-rected p values of less than 0.001 with a cluster extent threshold of20 voxels and by corrected p value of less than 0.05 after the falsediscovery rate across the entire brain.

Finally, to ascertain the clusters related to task performance, a regionof interest correlation analysis was performed. Based on our hypothesisthat patients with schizophrenia would show altered activation in theprefrontal cortex and STS during social perception, we selected twoclusters in the DLPFC identified by the result of the group× appropriate-ness interaction and the STS identified by the appropriateness ×emotion interaction under each group. The % BOLD signal changes ofthe clusters were obtained using MarsBaR version 0.41 (http://marsbar.sourceforge.net/) and then non-parametric correlation analyses betweencluster activities and clinical scales in each group were done at a signifi-cance level of p-values less than 0.05. In these correlation analyses, theduration of illness and chlorpromazine equivalent dose were used ascovariates for the patient group.

2.4. Statistical analysis of the behavioral data

Demographic and clinical characteristics were compared betweengroups with independent-sample t-tests and chi-square tests. Accuracyand reaction time were analyzed using linear mixed model. The mainand interaction effects of group, appropriateness, and emotion wereincluded as fixed effects. In the post hoc analysis the least squaremeans of 3 emotionswere estimated by theMIXED procedure at appro-priate or inappropriate.

3. Results

3.1. Participants' characteristics and behavioral performances

As shown in Table 1, patients and controls did not significantly differin age, sex and educational level. However, patients showed lower gen-eral intellectual ability (p b 0.05) and higher social anhedonia scores(p b 0.05) than controls.

Accuracy and reaction time are shown in Table 2. The main effect ofaccuracy was found for group (F1,203 = 27.37, p b 0.001), but not forappropriateness and emotion. Post hoc analyses revealed that patientsanswered less correctly than controls (p b 0.001). The interaction effectwas found for the appropriateness × emotion (F2,203 = 3.26, p b .05).The statistic power for these positive results was 0.9 and 0.7 (α =0.05) with N95% confidence interval in the group effect and appropri-ateness × emotion interaction effect of accuracy, respectively. Themean differences between emotions for appropriate speech were 0.48(positive and neutral), 13.84 (positive and negative), and 13.36 (nega-tive and neutral). For inappropriate speech, however, the mean differ-ences between emotions were −0.30,−6.76, and −6.46, respectively.No significant interaction effect was found for group × appropriatenessor group × emotion, and group × appropriateness × emotion. For reac-tion time, there were no significant main or interaction effects.

3.2. Imaging findings

Imaging results of the main effects for group, appropriateness, andemotion are provided in Supplementary Table 1. On an analysis offunctional neuroimaging, data of three patients and one control wereexcluded due to a quality problem as bad slices were discarded usingArtRepair software. The main effect of group was found in a variety ofthe neocortical and subcortical regions, including the various prefrontalgyri, various temporal gyri, STS, supramarginal and angular gyrus,precuneus and cuneus, globus pallidus, and cerebellum. Themain effectof appropriatenesswas found in the relatively restricted regions, includ-ing the inferior frontal gyrus, middle temporal gyrus and precuneus.The main effect of emotion was also restricted to the precentral gyrus,middle temporal gyrus, caudate, and cerebellum.

http://marsbar.sourceforge.net/http://marsbar.sourceforge.net/

Table 1Demographic information about patients with schizophrenia and controls.

Patients Controls χ2/t P

(n = 17) (n = 19)

Age (years) 31.0 ± 6.1 28.21 ± 4.2 −1.609 0.117Sex (male/female) 11/6 12/7 0.009 0.923Education level (years) 13.8 ± 1.6 14.6 ± 3.0 1.006 0.321Intelligence quotient 98.7 ± 15 109.1 ± 12 2.270 0.030Social anhedonia scale (0–40) 13.4 ± 6.2 8.8 ± 3.9 −2.581 0.016PANSSPositive 17.1 ± 3.7Negative 17.3 ± 4.5General 32.6 ± 8.4

SC–LFS (0–36) 20.8 ± 5.5Duration of illness 10.9 ± 6.9Chlorpromazine equivalent dosage of antipsychotics (mg)⁎ 503.3 ± 226.4

PANSS, Positive and Negative Syndrome Scale; SC–LFS, Strauss–Carpenter Level of Functioning Scale.⁎ The medicine was amisulpride (2), aripiprazole (3), clozapine (3), haloperidol (1), olanzapine (3), paliperidone (1), quetiapine (1), and risperidone (4).

84 J.E. Shin et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

As presented in Table 3, the group× appropriateness interactionwasexhibited in the left DLPFC, right precentral gyrus and left supramarginalgyrus. In the post hoc test for the a priori regions, as shown in Fig. 2, leftDLPFC activity in the appropriate condition was not significantly differ-ent between the two groups, whereas left DLPFC activity in the inappro-priate conditionwas significantly lower in patients than in controls (t=2.6, p b 0.05). Correlation analysis revealed that left DLPFC activity inthe inappropriate condition was negatively correlated with the PANSSnegative scores (r = −0.650, p b 0.05) and positively correlated withthe SC-LFS scores (r = 0.691, p b 0.05), but not with any other scalescores. A group × emotion interaction was not found in any region.

An appropriateness × emotion interaction was observed in variousbrain regions including the right DMPFC, left DLPFC, left STS, right supe-rior temporal gyrus, several occipital regions, and right cerebellum. Anappropriateness × emotion interaction in each group indicated that dif-ferent regions were involved. In particular, as shown in Fig. 3, an appro-priateness × emotion interaction in the left STS was found in controls,but not in patients. Post hoc analysis revealed that left STS activity in pa-tients was significantly higher in the appropriate negative conditionthan in the appropriate positive condition (t = −3.1, p b 0.01), butnot significantly different between the inappropriate negative andinappropriate positive conditions. Left STS activity in controls was alsosignificantly higher in the appropriate negative condition than in theappropriate positive condition (t = −2.1, p b 0.05), but significantlylower in the inappropriate negative condition than in the inappropriatepositive condition (t = 3.9, p b 0.01).

4. Discussion

In thepresent study,we investigated thebrainmechanisms involvedin perceiving appropriateness and emotion in social situations. Usingthe MR-compatible virtual reality system, we presented diverse socialsituations to participants. Previously, our research group demonstrated

Table 2The accuracy and reaction time for the virtual social perception task (mean ± standarddeviation).

Patients (n = 17) Controls (n = 19)

Appropriate Inappropriate Appropriate Inappropriate

Accuracy (%)Positive 71.43 ± 30.91 63.31 ± 37.86 89.72 ± 10.07 82.21 ± 32.06Neutral 69.75 ± 28.02 61.06 ± 33.77 90.48 ± 9.12 84.96 ± 30.21Negative 58.82 ± 28.07 67.79 ± 31.25 74.44 ± 28.58 91.23 ± 16.21

Reaction time (ms)Positive 722.88 ± 291.65 704.26 ± 244.07 672.25 ± 324.75 691.77 ± 330.59Neutral 676.69 ± 280.83 722.01 ± 235.16 685.49 ± 336.77 663.87 ± 332.05Negative 784.25 ± 239.88 705.85 ± 286.88 727.74 ± 336.22 655.22 ± 330.45

that such a virtual reality system was useful in assessing social percep-tion of patients with schizophrenia as well as normal subjects (Kimet al., 2007). In the diverse social situations of daily lives, participantsdifferently responded according to the conditions. Particularly, low ac-curacy in the appropriate negative condition suggests that both patientsand controls might consider negative events to be unfamiliar and un-comfortable because bad news and unlucky events happen less oftenthan ordinary ones and occur suddenly, and thus both groupsmight per-ceive situationswith neutral or positive contents as being relativelymorecomfortable and natural. In contrast, high accuracy for inappropriatenegative speech suggests that such a condition seems to make bothgroups feel awkward.

The most characteristic group difference while experiencing the so-cial situationswas found in the left DLPFC. Significantly decreased activ-ity in the left DLPFC was found during the inappropriate condition inpatients compared to controls. Previous studies have recognized thatthe DLPFC plays an important role in various cognitive processes (Liuet al., 2004; MacDonald et al., 2000). Typically, this region is engagedin cognitive flexibilitywhen people face new and unexpected situationsto restructure knowledge in multiple ways (Kim et al., 2011a; Gu et al.,2008) and in abstract thinkingwhen regarding situations in general andsymbolicmodes (Harrow et al., 1974). The role of theDLPFC in cognitivecontrol has been shown in social situations of inconsistent conditions(Weissman et al., 2008). Therefore, our finding of DLPFC hypoactivityin patients suggests that impairment in perceiving socially unusualsituations may stem from dysfunction in cognitive control. This viewis supported by previous findings that patients with schizophreniaexpressed cognitive rigidity in real life (Han et al., 2012) and abnormalabstract thinking, which was associated with impaired DLPFC function(Berman et al., 1988).

In addition, our study showed that DLPFC activity in patients had anegative correlation with the severity of negative symptoms and a pos-itive correlationwith the level of social functioning. Decreasedmetabol-ic activity in the DLPFC has been considered to be a core feature relatedto the predominance of negative symptoms in schizophrenia (Potkinet al., 2002; Wolkin et al., 1992). Cortical volumetric abnormalities inthe DLPFC and disruption of the white matter tracts connecting to theDLPFC have also been regarded as a major feature of deficit schizophre-nia, which is characterized by the presence of primary and enduringnegative symptoms (Fischer et al., 2012; Voineskos et al., 2013). Deficitschizophrenia has been associatedwith greater impairment in cognitiveability and social cognition (Cohen et al., 2007; Csukly et al., 2014; Volpeet al., 2012). In particular, negative symptoms include an inclinationtoward stereotyped thinking (Piskulic and Addington, 2011) and areclosely related to social functioning (Hunter and Barry, 2012). Therefore,DLPFC hypoactivity-related cognitive inflexibility may lead to socialdysfunction in patients with schizophrenia (Carrion et al., 2011; Hunterand Barry, 2012). Taken together, DLPFC dysfunction in schizophrenia

Table 3Brain regions showing the significant interaction effect of group, appropriateness, and emotion.

Regions (BA) Voxels MNI Coordinates F

x y z

Group × AppropriatenessDorsolateral prefrontal cortex (8)* 25 −22 44 36 15.2Precentral gyrus (6) 80 50 −4 40 22.8Supramarginal gyrus (40) 23 −58 −40 36 14.4

Group × EmotionNone

Appropriateness × EmotionDorsomedial prefrontal cortex (8)* 79 8 32 48 17.1

58 0 56 30 16.5Dorsolateral prefrontal cortex (9)* 22 −46 8 26 16.5

39 −56 20 28 14.5Superior temporal sulcus (22)* 107 −56 −18 −2 20.0Superior temporal gyrus (22) 21 48 −50 2 14.2Inferior occipital gyrus (17)* 418 −10 −98 −6 29.7Fusiform gyrus (37)* 651 −52 −64 −18 22.4Cuneus (17) 30 28 −78 10 17.4Cerebellum* 489 36 −66 −22 19.5

Appropriateness × Emotion in patientsCerebellum 60 −44 −50 −22 27.0

Appropriateness × Emotion in controlsSuperior temporal sulcus (22)* 110 −56 −18 −4 30.2Lingual gyrus (18) 242 −12 −90 −8 23.6Cuneus (17) 61 28 −78 10 20.0Cerebellum 33 10 −82 −32 17.4

Presented regions had a threshold of uncorrected p b 0.001 and more than 20 voxels. *Regions which survived after false discovery rate corrected p b 0.05.

85J.E. Shin et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

may reflect a deficit in cognitive control during social perception, whichcontributes to negative symptoms and decreased social functioning.

Another region showing a noteworthy feature was the left STS, inwhich the interaction effect between appropriateness and emotionwas present in controls, but absent in patients. In the appropriate con-dition, both groups showed significantly higher left STS activity inresponse to negative speech than to positive speech. This feature of ac-tivity may be connected to the behavioral observation that accuracy for

Fig. 2. (A) Dorsolateral prefrontal cortex (DLPFC) activity showing the interaction of group× appcontrols, and (B) correlations of DLPFC activity in the inappropriate condition with the severity

appropriate speech was significantly lower in negative speech than inpositive speech. The STS is activated by passive viewing of biologicalmotion (Puce et al., 1998), and is further engaged in analyzing the inten-tions of observed biological motions (Lahnakoski et al., 2012; Pelphreyet al., 2004). STS activity tends to be increased in unexpected comparedto expected situations (Ahmed andVanderWyk, 2013). In the appropri-ate situations of our experiment, positive speech appeared to be experi-enced as typical, in contrast to the perception of negative speech as

ropriateness and the comparison of DLFPC activity in each condition between patients andof negative symptoms and the level of social functioning (*p b .05).

Fig. 3. Left superior temporal sulcus activity showing the interaction of appropriateness and emotion that exists only in controls, and the comparison of signal changes in the superiortemporal sulcus based on conditions in each group (* p b .05, ** p b .01).

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being a relatively uncommon occurrence. This situational unusualnessof appropriate but negative speech might have led to the discrepancyin response accuracy and STS activity, with both patients and controlsacting in a similar fashion under this appropriate condition. In the inap-propriate condition, however, controls demonstrated significantlyhigher STS activity in response to positive speech than to negativespeech, whereas patients showed no difference between the two condi-tions. This reverse finding in controls led to an interaction effect be-tween appropriateness and emotion in the left STS, which is consistentwith the previous notion that the STS plays a key role in the interactiveprocessing of social and emotional information (Norris et al., 2004).Given that STS activity is sensitive to the congruency between observedaction and emotion (Wyk et al., 2009), the different STS features be-tween the appropriate and inappropriate conditions in controls maybe additional evidence for the role of this region in analyzing the inten-tion of others. Furthermore, the absence of this conditional difference inpatients seems consistent with their difficulties in discriminating bio-logical motion (Kim et al., 2011b; Spencer et al., 2013; Thakkar et al.,2014). Consistently, our research group has recently reported thatpatients with schizophrenia did not show normal STS hyperactivity ina socially interactive situation that was designed to simulate social re-jection (Lee et al., 2014), supporting the presence of patients' deficitsin the perception of social acts.

In contrast to our expectations, MPFC activity was not significantlydifferent between patients and controls in our study. The MPFC hasbeen regarded as a representative brain region in the theory of mindnetwork together with the STS (Bosia et al., 2012). In particular, theMPFC has been implicated in mentalization, such as making inferencesabout others' intentions andmental states, and attributions of emotionsto self and others (Frith and Frith, 1999; Ochsner et al., 2004). The ab-sence of a positive finding in this region could be attributed to a charac-teristic of our task for measuring social perception in daily life thatmight recruit cognitive control or cognitive flexibility rather thanmentalization. In other words, our social perception task may provokeactivation of the DLPFC-STS network rather than the MPFC-STS

network. Dysfunction of theDLPFC-STS network is striking in the salientstimuli such as inappropriate situations, though there is no direct evi-dence of connectional dysfunction between these two regions in ourfindings. However, since abnormal connectivity between the DLPFCand STS is important in individuals with autism spectrum disorder(Wicker et al., 2008), it is possible that impaired connectivity betweenthe two regions may underlie social perception dysfunction in patientswith schizophrenia. This interpretation is supported by another reporton schizophrenia, which demonstrated the inferior frontal gyrus-STSdisconnection during the processing of metaphoric gestures (Straubeet al., 2014).

There are some limitations in our study. The generalizability of ourresults may be limited due to the relatively small sample size. Becauseall patients in our study were medicated and we did not evaluate theside effects of the antipsychotic medications, the effects of the antipsy-chotics could not be excluded from the results. Further studies includingdrug-naïve patients need to be done to avoid the confounding effects ofmedication. Another limitation is that social functioning was assessedonly by the SC-LFS. Many social functioning scales, which greatly varyin terms of thenumber and types of domains, have beenused for schizo-phrenia studies (Burns and Patrick, 2007). The SC-LFS includes domainsof interpersonal and occupational function but has a weakness in per-sonal domains. In addition, although cognitive control or flexibilitywas considered to be an important factor in social perception, executivefunctions were not evaluated. Given that there was a significant differ-ence in general intelligence between patients and controls, executivefunctions would be different between the two groups and this differ-ence could affect the performances.

In summary, we investigated the neural basis of social perceptiondysfunction in daily life of patients with schizophrenia and its relation-ship with their clinical symptoms and social functioning. The resultsprovide useful information on the important role of the DLPFC in socialperception and its relationship with negative symptoms and socialdysfunction in patients with schizophrenia. The findings also affirmthe key role of abnormal STS activity in social perception dysfunction

87J.E. Shin et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 81–88

in schizophrenia. These results suggest the possibility that dysfunctionof the DLPFC-STS network may underlie patients' abnormal social per-ception in various social situations of daily life.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.pnpbp.2014.12.006.

Contributors

SHC and JJK designed the study. SHC, HL and YSS collected the orig-inal imaging data. JES, YSS and DPJ managed and analyzed the imagingdata. JES and JJK wrote the first draft of the manuscript. All authorscontributed to and have approved the final manuscript.

Acknowledgments

This work was supported by the National Research Foundation ofKorea (NRF) grant funded by the Korea government (MEST) (No. NRF-2013R1A2A2A03068342). We would like to thank Dr. Kang Joon Yoonand Mr. Sang Il Kim for his valuable technical support.

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Involvement of the dorsolateral prefrontal cortex and superior temporal sulcus in impaired social perception in schizophrenia1. Introduction2. Methods2.1. Participants and clinical measurements2.2. Experimental design2.3. MRI acquisition and analysis2.4. Statistical analysis of the behavioral data

3. Results3.1. Participants' characteristics and behavioral performances3.2. Imaging findings

4. DiscussionContributorsAcknowledgmentsReferences